This invention relates to steroid compounds and pharmaceutical acceptable salts thereof, a method for preparation thereof, pharmaceutical compositions containing the same as active component, and their use in the preparation of medicines for treating diseases associated with progestogen dependence and for fertility control, abortion or contraception and for anticancer use.
Mifepristone (11xcex2-[4-(N,N-dimethylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene -3-one) is a steroid compound which is disclosed in French Patent No. 2, 497, 807 to Rousell-Uclaf, published May 31, 1983. It is the first progesterone receptor antagonist put into clinical application and is a new type of anti-progestin. It binds to progesterone receptor and glucocorticoid receptor, having an affinity with progesterone receptor in rabbit endometrium five-fold higher than that of progesterone and thereby having strong anti-progesterone effect. It causes degeneration of pregnant villus tissue and decidual tissue, endogenous prostaglandin (PG) release, luteinizing hormone decrease, corpus luteum dissolution, and necrosis of embryo sac whose development depends on corpus luteum, leading to abortion. Therefore, it can be used as a non-surgical medicine for stopping early pregnancy. It can also be used, inter alia, in contraception and as an antineoplastic. (The Antiprogestin Steroid Ru486 and Human Fertility Control, 1985, New York: Plenum Press).
Onapristone (11xcex2-[4-(N,N-dimethylamino)phenyl]-17xcex1-hydroxy-17xcex2-(3-hydroxypropyl)-13xcex1-4,9-estradiene-3-one), is a steroid compound which is disclosed in German Patent No. 3, 321, 826 to Schering A G, published Dec. 20, 1984. It has a strong antiprogestin activity and can be used in abortion (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), anticancer (Breast Cancer Research and Treatment, 1989, 14:275-288), etc. It was reported that onapristone had toxicity to human liver (European Journal of Cancer, 1999, 35(2): 214-218).
Lilopristone (11xcex2-[4-(N,N-dimethylamino)phenyl]-17xcex1-[3-hydroxy-1(Z)-propenyl]-17xcex2-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in German Patent No. 3, 347, 126 to Schering A G, published Jul. 11, 1985. It has a strong antiprogestin activity and can be used in abortion, contraception (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), etc. It was reported that the clinical effect of lilopristone in stopping early pregnancy was only equivalent to that of mifepristone (Human Reproduction, 1994, 9(1): 57-63).
ZK112993 (11xcex2-(4acetylphenyl)-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in German Patent No. 3, 504, 421 to Schering A G, published Aug. 7, 1986. It has a potent antiprogestin activity and can be used in, inter alia, anticancer (Anticancer Res., 1990, 10: 683-688).
In European Patent No. 321, 010 to Akzo N V, The Netherland published Jun. 21, 1989 are disclosed xe2x80x9c11-arylsteroid compoundsxe2x80x9d having a strong antiprogestin activity.
An object of the invention is to provide a class of steroid compounds of pharmaceutical value, especially having antiprogestin effect.
Another object of the invention is to provide a method for preparation of the steroid compounds.
Still another object of the invention is to provide pharmaceutical compositions for treating diseases associated with progestin dependence, and for fertility control, abortion or contraception and neoplasm control.
A further object of the invention is to provide use of said steroid compounds and pharmaceutical compositions in the preparation of medicines for treating diseases associated with progestin dependence, and for fertility control, abortion or contraception and neoplasm control.
The steroid compounds of the present invention has the following general formula (I): 
wherein R1 is cyclohexyl or cycloheptyl, R2 is hydrogen or C1-C6 alkyl, R3 is hydrogen, C1-C6 alkyl or methylol, R4 is hydrogen or hydroxymethylene (xe2x95x90CHOH).
The compounds of the present invention can be existed in the form of their salts. Also, due to multiple asymmetric carbon atoms contained therein, there may be many isomers of the compounds. These salts and isomers all fall within the scope of compounds of the present invention sought for protection.
The compounds of formula (I) of this invention are preferably those wherein R2 is hydrogen or methyl and R3 is methyl or methylol.
More preferred compounds of the invention include:
11xcex2-[4-(N-methyl-N-cyclohexylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one,
11xcex2-[4-(N-cyclohexylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one,
2-hydroxymethylene-11xcex2-[4-(N-methyl-N-cyclohexylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one,
11xcex2-[4-(N-methyl-N-cyclohexylamino)phenyl]-17xcex1-(3-hydroxy-1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one,
11xcex2-[4-(N-cyclohexylamino)phenyl]-17xcex1-(3-hydroxy-1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one,
11xcex2-[4-(N-methyl-N-cycloheptylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one,
11xcex2-[4-(N-cycloheptylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one,
2-hydroxymethylene-11xcex2-[4-(N-methyl-N-cycloheptylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one,
11xcex2-[4-(N-methyl-N-cycloheptylamino)phenyl]-17xcex1-(3-hydroxy-1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one,
11xcex2-[4-(N-cycloheptylamino)phenyl]-17xcex1-(3-hydroxy-1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one.
The preparation method of the present invention includes the following single- or multi-step procedures:
1. Method for the preparation of 11xcex2-[4-(N-methyl-N-cyclohexylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one (VI) which includes the following steps:

4-bromo-N-methyl-N-cyclohexylaniline (II) is reacted with magnesium in tetrahydrofuran (THF) to obtain Grignard reagent of formula (III).

Compound of formula (IV) and the Grignard reagent of formula (III) prepared in step (1) are brought to an additive reaction to obtain compound of formula (V).

The compound of formula (V) prepared in step (2) is subjected to a Hydrolytic reaction to obtain compound of form (VI).
2. Method for preparation of 11xcex2-[4-(N-cyclohexylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one (XI) which includes the following steps:

4-bromo-N-cyclohexylaniline (VII) is first protected by trimethylchlorosilane, then reacted with magnesium in THF to obtain Grignard reagent of formula (IX).

Compound of formula (IV) and the Grignard reagent of formula (IX) prepared in step (1) are brought to an additive reaction to obtain compound of formula (X).

The compound of formula (X) prepared in step (2) is subjected to a hydrolytic reaction to obtain compound of formula (XI).
3. Method for preparation of 2-hydroxymethylene-11xcex2-[4-(N-methyl-N-cyclohexylamino)phenyl]-17xcex1-(1-propinyl)-17xcex2-hydroxy4,9-estradiene-3-one (XII) which includes a formylation reaction as follows: 
Compound of formula (VI) is subjected to a formylation reaction to obtain compound of formula (XII).
4. Method for preparation of 11xcex2-[4-(N-methyl-N-cyclohexylamino)phenyl)]-17xcex1-(3-hydroxy-1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one (XVII) which includes the following steps:

Compound of formula (XIII) and the Grignard reagent of formula (III) prepared in step (1) according to claim 13 are brought to an additive reaction to obtain compound of formula (XIV).

Compound of formula (XIV) prepared in step (1) and Grignard reagent of formula (XV) are brought to an additive reaction to obtain compound of formula (XVI).

The compound of formula (XVI) prepared in step (2) is subjected to a hydrolytic reaction to obtain compound of formula (XVII).
5. Method for preparation of 11xcex2-[4-(N-cyclohexylamino)phenyl]-17xcex1-(3-hydroxy-1-propinyl)-17xcex2-hydroxy-4,9-estradiene-3-one (XX) which includes the following steps:

Compound of formula (XIII) and Grignard reagent of formula (IX) are brought to an additive reaction to obtain compound of formula (XVIII).

The compound of formula (XVIII) prepared in step (1) and Grignard reagent of formula (XV) are brought to an additive reaction to obtain compound of formula (XIX).

The compound of formula (XIX) prepared in step (2) is subjected to a hydrolytic reaction to obtain compound of formula (XX).
The compounds of the present invention can be combined with pharmaceutically acceptable carriers, pharmaceutically acceptable auxiliaries or other medicines to obtain pharmaceutical compositions for use in treating diseases associated with progestin dependence, controlling fertility, abortion or contraception, controlling neoplasm, etc., for example, use in treating mammary cancer, oophoroma, endometrial carcinoma, meningioma, hysteromyoma, endometriosis, premenstrual syndrome, and Cushing""s Syndrome, and use in abortion and contraception, etc. The compounds of the invention, the pharmaceutical compositions containing them, and the use thereof in the preparation of medicines for treat diseases associated with progestin dependence all fall within the scope the present invention sought for protection.
The compounds of the present invention can be prepared as their pharmaceutically acceptable salts with proper acids. The proper acids which can be used to produce the pharmaceutically acceptable salts are, for example, inorganic acids, e.g. hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc; organic acids, e.g. formic acid, acetic acid, propanoic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc; alkyl sulfonic acid, e.g. methyl sulfonic acid, ethyl sulfonic acid, etc; aryl sulfonic acid, e.g. benzene sulfonic acid, p-toluene sulfonic acid, etc.
Pharmaceutical compositions containing the compounds of the invention comprise pharmaceutically effective amount of the compounds of the invention and pharmaceutically acceptable carriers or auxiliaries or other medicines that are compatible with the compounds of the present invention.
The pharmaceutically acceptable carriers and auxiliaries for the compounds of the invention or in the pharmaceutical compositions containing the same may be starch and derivatives thereof, cellulose and derivatives thereof, cyclodextrin and derivatives thereof, high molecular polymers, organic acids and their salts and esters, inorganic compounds such as inorganic calcium salts and oxides, higher alcohols, phospholipids, saccharides and other suitable materials.
The compounds of the invention and the pharmaceutical compositions containing the same may be in solid dosage forms such as tablets, capsules, drop pills, granules and suppositories, or may be in the form of liquid formulations such as injection, suspension, emulsion and solution, or may be in the form for percutaneous administration and also dosage forms having special effects such as sustained release, controlled release, targeted release and pulsed release.
The present inventors found that the compounds of the invention have good effects in treating diseases associated with progestin dependence and in fertility control, abortion or contraception and neoplasm control. Compared with mifepristone, the compounds of the present invention have better effects in killing tumor cells, inhibiting MNU-induced rat mammary cancer, and stopping early pregnancy and inhibiting implanation in rat.